Update on the neurobiology of schizophrenia: a role for extracellular microdomains

Abstract

The glutamate system includes presynaptic glutamatergic terminals, complex post-synaptic densities found on diverse types of neurons expressing glutamate receptors, as well as glutamate transporters and enzymes that facilitate the glutamate/glutamine cycle. Abnormalities of this system have been implicated in schizophrenia based on an accumulating body of evidence from postmortem, imaging, and preclinical studies. However, recent work has suggested that astrocytes may have more than a bystander role in the synchronization of neuronal responses in the brain. Converging evidence suggests that extrasynaptic glutamate microdomains are formed by astrocytes and may facilitate neuroplasticity via the modulation of extra-synaptic glutamate receptors on neuronal membranes within these domains. In this article the authors propose that the composition and localization of protein complexes in glutamate microdomains is abnormal in schizophrenia, leading to pathological neuroplastic changes in the structure and function of glutamate circuits in this illness.

Keywords: Glutamate; Microdomain; Protein complex; Schizophrenia.

Figure 1

The glutamate synapse. Glutamate is released by presynaptic terminals and removed from the synaptic cleft by a family of excitatory amino acid transporters (EAATs). Glutamate is converted to glutamine, which is shuttled back to the presynaptic terminal, converted to glutamate, and packaged for release. This process is called the glutamate/glutamine cycle.

Figure 2

Glutamate microdomains may be formed by specialized protein complexes found on plasma membranes in extrasynaptic regions where astrocytic and neuronal membranes are apposed to one another. Specific protein complexes that may help form these domains have been identified. One complex (1) comprised primarily of glutamate transporters and supporting molecules may limit diffusion of glutamate from the synaptic cleft, while another protein complex (2) may regulate extracellular glutamate levels in glutamate microenvironments (3) which in turn would modulate activation of extrasynaptic glutamate receptors on neurons and glia (4).